Antimicrobial Polymer for Use in Ophthalmic implants

ABSTRACT

An antimicrobial polymer for use in an ophthalmic implant, includes at least one antimicrobial monomer; and at least one other monomer selected from an acrylic, silicone, vinyl and collagen monomer.

FIELD OF THE INVENTION

The present invention relates generally to ophthalmic implant devicesand methods for their preparation and use, and more particularly, toantimicrobial polymers, obtained by copolymerizing at least oneantimicrobial monomer with at least one other monomer for use in anophthalmic implant device.

BACKGROUND OF THE INVENTION

Infections are serious complications of ophthalmic implant surgery.Examples of ocular implants include intraocular lenses, glaucoma valves,and artificial corneas, which are also known as keratoprostheses. Anuncontrolled infection after ophthalmic implant surgery of any of thesedevices can result in loss of vision or even loss of the eye.

It is important to distinguish ophthalmic implants from contact lenses.Although both are considered medical devices, their purpose andrequirements for proper functioning are very different.

Contact lenses are clear lenses that float on the human tear film. Theyare not physically attached to the eye in any way and direct contactbetween the contact lens and tissue is known to cause complicationsincluding corneal abrasions, infections and corneal scarring. A contactlens' purpose is to refract light to allow proper focus of light raysonto the retina.

By contrast, an ophthalmic implant is any device; clear, translucent oropaque, that can be embedded inside ocular tissue. An ophthalmic implantmust be biocompatible with the ocular tissues in order to function.

The most common strategy used in reducing the risk of infection afterophthalmic implant surgery is the use of topical antibiotic drops.However, this regimen has the significant disadvantage of needing torely on the patient's compliance to insure that the medications aredosed properly. The infection issue is especially troublesome in thecase of artificial cornea implants, which currently require the dailyadministration of topical antibiotics drops for the life of the patient.The use of such antibiotics is necessary because current artificialcorneas are exposed to the non-sterile surface of the eye. As such,there is a continual risk of infection.

Other inventors have recognized the inadequacy of antibiotic medicationsas a method of reducing infection after ophthalmic implant surgery. Onealternative strategy that has been proposed is to either coat orcovalently bond antibacterial chemicals to the surface of the ophthalmicimplant as disclosed in U.S. Pat. No. 6,976,997 issued to Noolandi etal. A limitation of this method is that coatings and covalently bondedchemicals can be eroded away from the surface of the implant over time.Therefore, it is predictable that the antibacterial properties of thesetypes of implants will decrease over time thereby increasing the risk ofinfection.

Another strategy, which has been proposed in the past, is to infuse thepolymer of the ophthalmic implant with an antibacterial metal ion. Inparticular, silver and copper metal have been proposed as agents to beinfused into polymers for use in an ophthalmic implant. Although, theuse of free metal ions as an antibacterial agent within polymers hasbeen used widely in commercial plastic goods and in some short-termdisposable medical devices such as catheters, metal ions are known to bedangerous in the eye.

Argyrosis is the medical term for silver toxicity of the eye. Argyrosishas been reported to result in a slate gray discoloration of theconjunctiva and iris. Argyrosis has also been found to result incataracts and retinal maculopathy, both of which are vision threateningconditions.

Copper toxicity in the eye results in a characteristic green ring aroundthe cornea, which is termed a Kayser-Fleischer ring. Moreover, studieshave demonstrated that copper toxicity can induce ocular complicationssuch as intraocular inflammation (uveitis), hemorrhage, vitreousliquefaction, hypotony, iris ischemia and retinal damage.

In addition, free metal ions may also leach out of the polymer over timeand therefore, the polymer may lose its antimicrobial properties overtime.

For the stated reasons, there remains a need in the art for an improvedcomposition and method of decreasing the risk of microbial infectionsafter ophthalmic implant surgery.

SUMMARY OF THE INVENTION

The invention provides antimicrobial polymers for use in an ophthalmicimplant obtained by copolymerizing at least one antimicrobial monomerand at least one monomer selected from an acrylic, silicone, vinyl orcollagen monomer. The invention also provides methods for preparing anantimicrobial polymer for use in an ophthalmic implant, by reacting atleast one antimicrobial monomer with at least one other monomer selectedfrom an acrylic, silicone, vinyl and collagen monomer to provide theantimicrobial polymer; and using the antimicrobial polymer in theophthalmic implant.

The copolymers of the present invention are antimicrobial,biocompatible, and reversibly deformable and are also clear, translucentor opaque. These characteristics are desirable for the optimal functionof ophthalmic implants that are designed for implantation inside oculartissue through small incisions. Moreover, because the entire co-polymer,not just the surface of the co-polymer, has antimicrobial properties,ophthalmic implants made from these types of co-polymers will not losetheir antimicrobial properties even if the surface of the implantbecomes eroded over time. This is particularly important for ophthalmicimplants that are exposed to the surface of the eye, where blinking willcause erosion of the polymeric material. When the surface of the polymerof the present invention is eroded, the antimicrobial polymer beneaththe surface will still kill microbes and thereby decrease the infectionrisk for the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates an embodiment of the polymerization of anantimicrobial, clear, biocompatible, reversibly deformable polymer.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure provides antimicrobial polymers for use inophthalmic implants, which are obtained by copolymerizing at least oneantimicrobial monomer with at least one other monomer selected from anacrylic, silicone, vinyl or collagen monomer. The resultingantimicrobial polymer provides an antimicrobial, biocompatible, andreversibly deformable implant, which are also clear, translucent oropaque. These characteristics are desirable for the optimal function ofophthalmic implants that are designed for implantation inside oculartissues through small incisions. Moreover, because the entire copolymer,not just the surface of the copolymer, has antimicrobial properties,ophthalmic implants made from this type of copolymer will not lose theirantimicrobial properties even if the surface of the implant becomeseroded over time. This is particularly important for ophthalmic implantswhich are exposed to the surface of the eye, where blinking will causeerosion of the polymeric material.

There are many types of ophthalmic implants. One type of such implant isan artificial cornea. In an artificial cornea the copolymer iscontemplated to be antimicrobial, clear, biocompatible and reversiblydeformable. In some cases, ophthalmic implants do not need to be clearto perform their intended function. For example, glaucoma valves,retinal prostheses and intracorneal implants outside of the visual axisdo not need to refract light as part of their function and therefore,they may be translucent or opaque. In these cases the polymer of thepresent invention may be translucent or opaque. Various ophthalmicimplants and methods thereof, have been fully described in U.S. Pat.Nos. 8,029,515; 7,901,421; and 7,223,275, each of which are herebyincorporated by reference in their entireties for all purposes.

Antimicrobial polymers are a class of polymers having antimicrobialactivity, or the ability to inhibit the growth of microorganisms such asbacteria, fungi and/or protozoans. These polymers mimic antimicrobialpeptides, which are used by the immune systems of living animals to killvarious microbes. Antimicrobial polymers are generally nonvolatile andchemically stable, and are used in the areas of medicine as a means tofight infection, in the food industry to prevent bacterialcontamination, and in water sanitation to inhibit the growth ofmicroorganisms in drinking water.

Antimicrobial polymers kill microorganisms on contact by causing theircells to burst. For example, antimicrobial polymers generally possess apositive charge, and can be readily adsorbed onto the negative surfaceof the cell wall of a bacteria. Once adsorbed, the antimicrobial polymerthen diffuses through the cell wall where it binds to and disrupts thecell membrane. While adsorption is best achieved by cationicantimicrobial polymers, small molecule antimicrobial agents excel atdiffusion due to their low molecular weight. The disruption of the cellmembrane and subsequent leakage of cytoplasmic constituents leads to thedeath of the bacteria.

Most bacterial cell walls are negatively charged and therefore, mostantimicrobial polymers are positively charged to facilitate theadsorption process. The structure of the counter ion, or the ionassociated with the polymer to balance charge, also affects theantimicrobial activity. Counter anions that form a strong ion-pair withthe polymer impede the antimicrobial activity because the counter ionprevents the polymer from interacting with the bacteria. However, ionsthat form a loose ion-pair or readily dissociate from the polymer,exhibit a positive influence on the activity because it allows thepolymer to interact freely with the bacteria.

FIG. 1 illustrates an embodiment of the polymerization of anantimicrobial, clear, biocompatible, reversibly deformable polymer. Inthis figure, the antimicrobial polymers are obtained by copolymerizingat least one antimicrobial monomer with at least one monomer selectedfrom an acrylic, silicone, vinyl or collagen monomer. Afterpolymerization, the resulting polymeric network includes the immobilizedantimicrobial polymer spaced throughout the network.

In an embodiment, the antibacterial monomer is selected from quaternaryammonium salt based monomers. A non-limiting example of a quaternaryammonium salt based monomer is 1-[12-(methacryloyloxy)dodecyl]pyridiniumbromide (MDPB):

CH₂═C(CH₃)C(O)O(CH₂)₁₂ N ⁺(C₅H₅) Br⁻  MDPB

MDPB has been used as an antimicrobial monomer to reduce the risk ofdental caries when copolymerized with dental adhesives and dentalresins.

In other embodiments, the least one antimicrobial monomer is aquaternary ammonium salt based monomer such as methacryloxylethyl cetyldimethyl ammonium chloride (DMAE-CB).

CH₂═C(CH₃)C(O)O(CH₂)₂ N ⁺(CH₃)₂(CH₂)₁₅CH₃ Cl⁻  DMAE-CB

It is also possible to increase the amount of antibacterial monomersthat can be incorporated into polymeric materials and subsequentlyenhance the antibacterial activity by modifying the quaternary ammoniumsalt based monomers to have two polymerizable methacrylic moieties.

Thus, in other embodiments, the least one antimicrobial monomer is aquaternary ammonium salt based monomer such as 2-methacryloxyethyldodecyl methyl ammonium bromide (MAE-DB):

CH₂═C(CH₃)C(O)O(CH₂)₂ N ⁺(CH₃)(CH₂)₂O(O)CC(CH₃)═CH₂(CH₂)₁₂CH₃Br⁻  MAE-DB

In other embodiments, the least one antimicrobial monomer is aquaternary ammonium salt based monomer such as 2-methacryloxyethylhexadecyl methyl ammonium bromide (MAE-HB):

CH₂═C(CH₃)C(O)O(CH₂)₂N⁺(CH₃)(CH₂)₂O(O)CC(CH₃)═CH₂(CH₂)₁₆CH₃Br⁻  MAE-HB

In other embodiments, the least one antimicrobial monomer is aquaternary ammonium salt based monomer such as bis(2-methacryloxyethyl)dimethyl ammonium bromide (IDMA-1):

CH₂═C(CH₃)C(O)O(CH₂)₂ N ⁺(CH₃)₂(CH₂)₂O(O)CC(CH₃)═CH₂Br⁻  IDMA-1

In other embodiments, the at least one antimicrobial monomer may differbased on the alkyl chain length. Examples of these include but are notlimited to dimethylamino propyl methacrylate (DMAPM), dimethylaminohexyl methacrylate (DMAHM), dimethylamino heptyl methacrylate (DMAHPM),dimethylamino octyl methacrylate (DMAOM), dimethylamino nonylmethacrylate (DMANM), dime thylamino decyl methacrylate (DMADM),dimethylamino undecyl methacrylate (DMAUDM), dimethylamino dodecylmethacrylate (DMADDM), dimethylamino tridecyl methacrylate (DMATDM),dimethylamino tetradecyl methacrylate (DMATTDM), dimethylaminopentadecyl methacrylate (DMAPDM), dimethylamino hexadecyl methacrylate(DMATDM), dimethylamino heptadecyl methacrylate (DMAHPDM), dimethylaminooctadecyl methacrylate (DMAODM), dimethylamino nonadecyl methacrylate(DMANDM), dimethylamino icosyl methacrylate (DMAIOM), dimethylaminohenicosyl methacrylate (DMAHOM), dimethylamino docosyl methacrylate(DMADOM), and/or combinations thereof.

In other embodiments, the antimicrobial monomer may have a primary,secondary or tertiary amino group. Examples of these types ofantibacterial monomers include but are not limited to ortho-, meta-,and/or para-dimethylaminomethyl styrene,N-[2-dimethylamino)ethyl]acrylamide, N-(2-aminoethyl)acrylamide,n-butylacrylamide, and diallyldimethyl ammonium salts.

In yet other embodiments, the antimicrobial monomer may be covalentlylinked to an antimicrobial peptide. Examples of antimicrobial peptidesinclude but are not limited to: β-sheet peptides stabilized by two tofour disulfide bridges (e.g., human α- and β-defensins, plectasin orprotegrins); α-helical peptides (e.g., LL-37, cecropins or magainins);extended structures rich in glycine, proline, tryptophan, arginine orhistidine (e.g., indolicidin); and loop peptides with one or disulfidebridge (e.g., bacteriocins).

In an embodiment, the at least one other monomer is selected from anacrylic, silicone, vinyl, or collagen monomer. These monomers canundergo polymerization with the at least one antimicrobial monomerdescribed above to provide the antimicrobial polymers for use inophthalmic implants. For example, the ophthalmic implant may be formedfrom a single blank or block of material typically a polymeric ishydrogel of a type commonly employed in forming intraocular lenses(IOUs), such as a copolymer of hydroxyethyl methacrylate and methylmethacraylate, or a hydrophobic acrylic material. The polymerichydrogel material could also have both hydrophobic and hydrophilicproperties, such as a copolymer of hydroxyethyl methacrylate andmethylmethacraylate that has undergone plasma surface treatment.Alternatively, the ophthalmic, plant could be molded, machined, or lasercut from a collagen-based hydrogel.

In embodiments, the at least one other monomer is biocompatible with thecornea, the eye and the body. Suitable monomers include but are notlimited to one or more monomers selected from collagen, urethanes,(2-hydroxyethylmethacrylate), vinylpyrolidone, glycerolmethacrylate,vinyl alcohol, ethylene glycol, methacrylic acid, silicones, acrylics,fluorocarbons, and monomers with phosphocholine.

In an embodiment, the at least one other monomer comprises a hydrogel.In other embodiments, the material comprises methacrylic acid andhydroxyethyl methacrylate (PHBMA/MAA).

In other embodiments, the at least one other monomer is a materialcomprising a reversibly deformable acrylic monomer, such as those usedfor intraocular lenses. Examples of suitable monomers include but arenot limited to hydroxyethyl methacrylate and methyl methacrylate. Inadditional aspects, the monomers provide a deformable polymer that ishydrophilic in nature in order to allow smooth wetting of the opticalsurface of the implant. Wetability is an important characteristic of anophthalmic implant to allow the tear film to act as a good opticalinterface.

In yet other embodiments, the ophthalmic implant may be manufacturedfrom monomers that promote epithelialization on the surface of theimplant. Examples of such materials include collagen andN-isopropylacrylamide, collagen and1-ethyl-3.3′(dimethyl-aminopropyl)-carbodiimide as well as collagen andN-hydroxysuccinimide (EDC/NHS). In other aspects, the polymer mayadditionally contain extracellular matrix proteins such as fibronectin,laminin, substance P, insulin-like growth factor-1, or peptide sequencessuch as fibronectin adhesion-promoting or peptide (FAP).

In an embodiment, the at least one other monomer is an acrylic monomer.Non-limiting examples of an acrylic monomer include but are not limitedto methyl acrylate (MA) and methyl methacrylate (MMA). MA and MMA areorganic compounds having formula: CH₂═CHCO₂CH₃ and CH₂═C(CH₃)CO₂CH₃,respectively. These colorless liquids are produced on a large scale forthe production of poly(methacrylate) (PMA) and poly(methyl methacrylate)(PMMA), respectively. While MA and MMA are irritants and possiblycarcinogenic, polymers of MA and MMA are biocompatible, resistant tolong exposure to temperatures, and the chemistry and cell action ofhuman tissues. Acrylic monomers can undergo polymerization with the atleast one antimicrobial monomer described above to provide theantimicrobial polymers for use in ophthalmic implants.

In an embodiment, the at least one other monomer is a silicone.Silicones have formula: R₂SiO, where R is an organic group such asmethyl, ethyl, or phenyl. Silicones can undergo polymerization to formpolysiloxanes, which include a repeating inorganic silicon-oxygenbackbone chain (—Si—O—Si—O—Si—O—) with the organic side group R attachedto the tetravalent silicon atom. By varying the —Si—O— chain lengths,side groups, and cross linking, polysiloxanes can be synthesized with awide variety of properties and compositions. They can vary inconsistency from liquid to gel to rubber to hard plastic. The mostcommon siloxane is the linear polydimethylsiloxane (PDMS), a siliconeoil. Silicone monomers can also undergo polymerization with the at leastone antimicrobial monomer described above to provide the antimicrobialpolymers for use in ophthalmic implants.

In an embodiment, the at least one other monomer is a vinyl monomer.Non-limiting examples of a vinyl monomer include but are not limited tovinyl esters (acrylates), vinyl carbonates (ROC(O)OCH═CH₂), and vinylcarbamates (R′R″NC(O)OCH═CH₂). These monomers have been shown to begenerally suitable for many biomedical applications. In particular,monomers like vinyl carbonates and vinyl carbamates generally have lowercytotoxicity yet similar reactivity to acrylates. For example,degradation vinyl carbonates and vinyl carbamates can be easily tuned toprovide non-toxic low molecular weight polyvinyl alcohol as degradationproduct and various other non-toxic alcohols such as glycerol orpolyethylene glycol. This concept has also been used to provide vinylester derivatives of hyaluronic acid and gelatin in the field ofhydrogels for tissue engineering. Vinyl monomers can also undergopolymerization with the at least one antimicrobial monomer describedabove to provide the antimicrobial polymers for use in ophthalmicimplants.

In an embodiment, the at least one other monomer is a collagen monomer.A single collagen molecule, tropocollagen, is used to make up largercollagen aggregates, such as fibrils. Fibrils are made up of threepolypeptide strands, each of which has the confirmation of a left-handedhelix. These three left-handed helices are twisted together into aright-handed triple helix or microfibril, a cooperative quaternarystructure stabilized by hydrogen bonds. Each microfibril is theninterdigitated with its neighboring microfibrils. Moreover, collagenmonomers may be linked to one or more acrylate or vinyl monomers usingvarious linkers. Collagen monomers can also undergo polymerization withthe at least one antimicrobial monomer described above to provide theantimicrobial polymers for use in ophthalmic implants. In an embodiment,the ophthalmic implant may include collagen and N-isopropylacrylamide,collagen and 1-ethyl-3,3′(dimethyl-aminopropyl)-carbodiimide as well ascollagen and N-hydroxysuccinimide (EDC/NHS).

In the preceding description, the present disclosure is described withreference to specifically exemplary embodiments thereof. It will,however, be evident that various modifications and changes may be madethereto without departing from the broader spirit and scope of thepresent disclosure, as set forth in the claims. The specification anddrawings are, accordingly, to be regarded as illustrative and not asrestrictive. It is understood that the present disclosure is capable ofusing various other combinations and embodiments and is capable of anychanges or modifications within the scope of the inventive concept asexpressed herein.

What is claimed is:
 1. An antimicrobial polymer for use in an ophthalmicimplant, comprising at least one antimicrobial monomer; and at least oneother monomer selected from an acrylic, silicone, vinyl and collagenmonomer.
 2. The antimicrobial polymer according to claim 1, wherein theantimicrobial polymer is clear, opaque, or translucent.
 3. Theantimicrobial polymer according to claim 1, wherein the antimicrobialpolymer is reversibly deformable.
 4. The antimicrobial polymer accordingto claim 1, wherein the ophthalmic implant is an artificial cornea, aglaucoma valve, a retinal prostheses, or an intracorneal implant.
 5. Theantimicrobial polymer according to claim 1, wherein the antibacterialmonomer is a quaternary ammonium salt based monomer.
 6. Theantimicrobial polymer according to claim 5, wherein the quaternaryammonium salt based monomer is 1-[12-(methacryloyloxy)dodecyl]pyridiniumbromide (MDPB), methacryloxylethyl cetyl dimethyl ammonium chloride(DMAE-CB), 2-methacryloxyethyl dodecyl methyl ammonium bromide (MAE-DB),2-methacryloxyethyl hexadecyl methyl ammonium bromide (MAE-HB),bis(2-methacryloxyethyl) dimethyl ammonium bromide (IDMA-1).
 7. Theantimicrobial polymer according to claim 1, wherein the antimicrobialmonomer comprises a monomer having a primary, secondary or tertiaryamino group.
 8. The antimicrobial polymer according to claim 7, whereinthe antimicrobial monomer is para-dimethylaminomethyl styrene,N[2-dimethylamino)ethyl]acrylamide, N-(2-aminoethyl)acrylamide,n-butylacrylamide, or a diallyldimethyl ammonium salt.
 9. Theantimicrobial polymer according to claim 1, wherein the antimicrobialmonomer is covalently linked to an antimicrobial peptide.
 10. Theantimicrobial polymer according to claim 1, wherein the at least oneother monomer is an acrylic monomer selected from methyl acrylate (MA)and methyl methacrylate (MMA); a silicone monomer having formula: R₂SiO,where R is as methyl, ethyl, or phenyl; or a vinyl monomer selected froma vinyl carbonate and a vinyl carbamate.
 11. A method of preparing anantimicrobial polymer for use in an ophthalmic implant, comprising:reacting at least one antimicrobial monomer with at least one othermonomer selected from an acrylic, silicone, vinyl and collagen monomerto provide the antimicrobial polymer; and using the antimicrobialpolymer in the ophthalmic implant.
 12. The method of preparing anantimicrobial polymer according to claim 11, wherein the antimicrobialpolymer is clear, opaque, or translucent.
 13. The method of preparing anantimicrobial polymer according to claim 11, wherein the antimicrobialpolymer is reversibly deformable.
 14. The method of preparing anantimicrobial polymer according to claim 11, wherein the ophthalmicimplant is an artificial cornea, a glaucoma valve, a retinal prostheses,or an intracorneal implant.
 15. The method of preparing an antimicrobialpolymer according to claim 11, wherein the antibacterial monomer is aquaternary ammonium salt based monomer.
 16. The method of preparing anantimicrobial polymer according to claim 15, wherein the quaternaryammonium salt based monomer is 1-[12-(methacryloyloxy)dodecyl]pyridiniumbromide (MDPB), methacryloxylethyl cetyl dimethyl ammonium chloride(DMAE-CB), 2-methacryloxyethyl dodecyl methyl ammonium bromide (MAE-DB),2-methacryloxyethyl hexadecyl methyl ammonium bromide (MAE-HB),bis(2-methacryloxyethyl) dimethyl ammonium bromide (IDMA-1).
 17. Themethod of preparing an antimicrobial polymer according to claim 11,wherein the antimicrobial monomer comprises a monomer having a primary,secondary or tertiary amino group.
 18. The method of preparing anantimicrobial polymer according to claim 17, wherein the antimicrobialmonomer is para-dimethylaminomethyl styrene,N-[2-dimethylamino)ethyl]acrylamide, N-(2-aminoethyl)acrylamide,n-butylacrylamide, or a diallyldimethyl ammonium salt.
 19. The method ofpreparing an antimicrobial polymer according to claim 11, wherein theantimicrobial monomer is covalently linked to an antimicrobial peptide.20. The method of preparing an antimicrobial polymer according to claim11, wherein the at least one other monomer is an acrylic monomerselected from methyl acrylate (MA) and methyl methacrylate (MMA); asilicone monomer having formula: R₂SiO, where R is as methyl, ethyl, orphenyl; or a vinyl monomer selected from a vinyl carbonate and a vinylcarbamate.